Poly-dipeptides produced from hexanucleotide repeats cause selective motor neuron hyperexcitability in ALS.

SignificanceThe GGGGCC hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 () gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS). Despite myriad studies on the toxic effects of poly-dipeptides produced from the repeats, the mechanisms underlying the selective hyperexcitability of motor cortex that characterizes the early stages of ALS patients remain elusive. Here, we show that the proline-arginine poly-dipeptides cause hyperexcitability in cortical motor neurons by increasing persistent sodium currents conducted by the Nav1.2/β4 sodium channel complex, which is highly expressed in the motor cortex. These findings provide the basis for understanding how the mutation causes motor neuron hyperactivation that can lead to the motor neuron death in ALS.